The optically active nitro alcohols of the present invention are novel substances obtained by the nitro-aldol reaction between nitromethane and benzaldehyde derivatives.
It is widely known that such a nitro-aldol reaction proceeds in the presence of a base. For example, in Japanese Patent Application Laid-Open No. 58-203950, there is disclosed the nitro-aldol reaction performed in the presence of triethylamine which gives a racemic modification of benznitro alcohol. And in Tetrahedron Letters (1975) p. 4057, there is disclosed the reaction between 2-chlorobenzaldehyde and nitroethane upper a catalyst of an optically active compound which gives an asymmetric nitro alcohol in which a substituent is a chloride.
Further, the present inventors has reported in Tetrahedron Letters (1993) Vol. 34, p. 2657 that the reaction between benzaldehyde and nitromethane under a catalyst of lanthanum-lithium-(R)-binaphthol complex at −50° C. gives (S)-1-phenyl-2-nitro ethanol in a yield of 84% (40% e.e.), and when carried out under a catalyst of samarium-lithium-(R)-binaphthol complex at −40° C., the reaction gives the same compound in a yield of 90% (62% e.e.) ((R) or (S) in the name of each compound represents R or S isomer, respectively, showing the compound's configuration).
The yields and optical purities described above, however, are not satisfactory ones. In addition, an asymmetric nitro-aldol reaction of benzaldehyde compounds having a hydroxyl group or those having a hydroxyl group with a protecting group has not been found yet and the reaction products, optically active 1-substituted phenyl-2-nitro alcohol derivatives, have not been known yet, either.
But at the same time, it is hoped now that pharmaceuticals produced from benznitro alcohol derivatives will be supplied in the form of a single optical isomer rather than in the form of a racemic modification. The reason is that, when only one type of structure is therapeutically effective, the other type of optically active substance is no better than impurities and likely to cause adverse effects. In order to meet such a demand, various types of asymmetric synthesis and optical resolution of a racemic modification have been carried out as a method of obtaining pharmaceuticals of optically active substances.
However, as described above, the nitro-group containing compounds (intermediates) of the present invention have not been known yet, and the only example is (S)-1-phenyl-2-nitroethanol, which has no substituent, reported by the present inventors. Accordingly, the process for producing a group of pharmaceuticals which are to be produced from optically active 1-substituted phenyl-2-nitro alcohol derivatives has not been known, either.
The optically active 1-substituted phenyl-2-amino alcohol derivatives of the present invention are a group of the compounds obtained from the novel optically active 1-substituted phenyl-2-nitro alcohol derivatives of the present invention.
On the other hand, as a method of producing optically active 1-substituted phenyl-2-amino alcohol derivatives, various types of asymmetric synthesis and optical resolution of a racemic modification have been carried out, and various processes for producing compounds similar to these ones have been also reported.
For example, as a method using optical resolution, in Japanese Patent Application Laid-Open No. 64-9979 (Japanese Patent Publication No. 4-48791), there is disclosed a method of producing (R) isomer of 2-amino-1-(3-chlorophenyl) ethanol from the racemic modification using N-(t-butoxycarbonyl)-D-alanine. And in Japanese Patent Application Laid-Open No. 2-85247, there is disclosed the method of subjecting the racemic modification of 2-amino-1-(4-chlorophenyl) ethanol to optical resolution using D-tartaric acid.
As a method using an asymmetric reduction reaction, for example, in Chemical and Pharmaceutical Bulletin (1995) vol. 43–5, p. 738, there is disclosed the process for producing (S)-1-phenyl-2-[N-(2-chloroethyl)] aminoethanol hydrochloride from 2-[N-(2-chloroethyl)] aminophenone hydrochloride.
And as a method using microorganisms, for example, in Chemistry Express (1989) vol. 4–9, p. 621, there is disclosed the process for producing optically active 2-amino-1-phenylethanol from 2-amino-1-phenylethanol and α-aminoacetophenone as raw materials by microorganisms of Staphyrococcus, Micrococcus, Rhodococcus, and Niseria. 
Further, in Japanese Patent Application Laid-Open No. 8-98697, there is disclosed the process for producing optically active 2-amino-1-phenylethanol derivatives from 2-amino-1-phenylethanol derivatives using various microorganisms.
With the method using optical resolution, however, even if optical resolution is carried out perfectly, the maximum yield expected is only 50% per reaction, and moreover, it is difficult to collect the optically active substances desired in a good yield. Accordingly, in order to improve the yield of optically active substances, it becomes necessary to further racemize unnecessary chiral compounds and to carry out optical resolution of the obtained racemic modifications repeatedly. Thus, using optical resolution can not produce the optically active substances desired effectively and industrially, therefore it can not be a satisfactory method.
Further, with the method using a usual hydrogen-reduction reaction of which typical example is the above asymmetric reduction reaction, unless the hydrogen pressure is high, the reaction often does not proceed. Thus the method is not appropriate, and moreover, since it has to use a special catalyst, the treatment of the catalyst has been a problem.
For the reduction reaction of optically active nitro alcohols, U.S. Pat. No. 5,099,067 reports that the reduction reaction of erythro/threo forms of β-nitro alcohol proceeds at room temperature by adding ammonium formate.
For example, in Japanese Patent Application Laid-Open No. 6-256270, the present inventors report that (S)-(−)-propranolol is obtained in a yield of 90% from (S)-3-(α-naphthoxy)nitropropane-2-ol in the presence of PtO2 at 50° C. under atmospheric pressure. Further, the present inventors report in Journal of the Organic Chemistry (1995) vol. 60, p. 7388 that 2-amino-1,3-alkyldiol is obtained in a yield of 71% in the presence of Pd—C.
These reduction reactions, however, are limited to the cases where the reduction reaction occurs on racemic modifications, and where, when the reaction occurs on optically active substances, a phenyl group has no substituent or only chlors as a substituent. There is no prior art known which is related directly to the reduction reaction intended by the present invention during which a steric structure of phenyl group having a hydroxyl group is maintained.
A racemic modification of 1-phenyl-2-aminoethanol is a known compound, for example, in Japanese Patent Application Laid-Open No. 58-203950, there is disclosed the synthetic method in which 1-(3,4-dihidroxyphenyl)-2-nitroethanol is subjected to a catalytic hydrogen addition reaction using Raney nickel to proceed the reduction reaction quantitatively, so as to obtain a racemic modification of 1-(3,4-dihidroxyphenyl)-2-aminoethanol; however, the disclosure makes no concrete reference to the optically active substances of 1-substituted phenyl-2-aminoethanol.
Thus, optically active 1-substituted phenyl-2-nitroethanol derivatives have not existed to date, and the products obtained by the reduction of the nitro group thereof, optically active 1-substituted phenyl-2-aminoethanol derivatives, have not been produced.
On the other hand, 1-substituted phenyl-2-aminoethanol derivatives are widely known compounds as a useful pharmaceutical intermediate.
For example, European Patent No. 0,006,735 specification describes that the intended pharmaceuticals can be synthesized by reacting a racemic and optically active amino alcohol compound with a carbonyl compound or a halide; however, actually disclosed in its embodiments is only the process for producing racemic sarmeterol by reacting a racemic amino alcohol compound with a carbonyl compound or a halide.
In U.S. Pat. No. 5,442,118 specification there is disclosed the process for producing (R)-albuterol and in European Patent Publication No. 0,422,889 specification there is disclosed the process for producing (R)-sarmeterol; however, their production process is long, and the intended compound is obtained from the optically active styrene oxane derivatives which have been obtained from acetophenone derivatives as a raw material. In these patents, there is no embodiment in which the optically active 1-substituted phenyl-2-nitroethanol derivatives of the present invention are used.
Thus, optically active 1-substituted phenyl-2-nitroethanol compounds have not existed to date, therefore, the process for producing optically active albutamin and optically active sarmeterol using optically active catechol amines obtained by the reduction of the nitro group thereof has not been known.